1. Field of the Invention
The present invention relates to improvements in the sulfoxide glycosylation method for forming glycosidic linkages in solution or on a polymeric support. These improvements increase yield, allow a broader variety of neighboring groups on glycosyl donors and reduce formation of undesired reaction byproducts.
2. Background of the Invention
The sulfoxide glycosylation reaction has been used to make oligosaccharides and other glycoconjugates both in solution and on polymeric supports. See, e.g., D. Kahne et al., J. Am. Chem. Soc., 1989, Vol. 111, page 6881; U.S. Pat. Nos. 5,635,612; 5,627,270; 5,639,866 and 5,700,916. Anomeric sulfoxides can be activated at low temperature with triflic anhydride, leading to rapid glycosylation of nucleophiles, including relatively unreactive nucleophiles. A basic outline of the sulfoxide glycosylation reaction is presented below in Scheme 1. 
The sulfoxide oxygen is believed to react with triflic anhydride to form a sulfonium species which ejects phenylsulfenyl triflate to produce an activated species which in turn acts as a glycosyl donor. The activated species reacts with a nucleophile, e.g., the alcohol shown in Scheme 1, to produce a glycoside. Typically, the sulfoxide is referred to as the xe2x80x9cglycosyl donorxe2x80x9d and the nucleophile as the xe2x80x9cglycosyl acceptor.xe2x80x9d
However, it has been observed that the sulfoxide glycosylation reaction is more complex than is suggested by Scheme 1. In some cases, the activated sulfoxide is extremely reactive at xe2x88x9278xc2x0 C., and yet is stable at room temperature. See D. Kahne et al. (1989). This behavior suggests that there are other reaction pathways that must be controlled in order to better control the outcome of glycosylation.
As shown in Scheme 1, phenylsulfenyl triflate (PhSOTf) is formed in glycosylation reactions conducted with triflic anhydride. PhSOTf is extremely electrophilic and has the potential to react with a variety of protecting groups, such as allyl ethers and p-methoxybenzyl ethers, and can also cause cleavage of anomeric sulfides. The potential for formation of undesired byproducts increases with the number of functional groups and protecting groups on the glycosyl acceptor.
Glycosylation reactions employing glycosides substituted by halo or other leaving groups at the anomeric position, and alkanoyl esters at the 2-position are known to produce undesired orthoester byproducts. See S. Sato et al., Tetrahedron Lett., 1988, Vol. 29, page 4097; H. Kunz and A. Harreus, Liebigs Ann. Chem., 1982, page 41. Sulfoxide glycosylations are believed to proceed through the same intermediate, and to produce orthoester byproducts when an alkanoyl ester is present at the 2-position.
An improved method for performing sulfoxide glycosylation reactions with reduced levels of byproducts would be useful, especially in preparation of complex glycosylated products such as glycopeptides, in which the diverse functionality often leads to reduced yields of glycosylated product.
This invention is directed to a method for forming a glycosidic linkage by: (a) contacting a glycoside bearing an anomeric sulfoxide group with a compound bearing a free hydroxyl group in the presence of an organic acid anhydride and a scavenger of sulfenyl esters; and (b) allowing a glycosylation reaction to proceed under conditions effective to produce the glycosidic linkage. In a preferred embodiment of the invention, the glycoside bearing an anomeric sulfoxide group is added to a mixture of the other reactants. In another preferred embodiment of the invention, a Lewis acid is also present in the reaction mixture.
This invention is further directed to a method for forming a glycosidic linkage by: (a) forming a solution comprising: a compound bearing a free hydroxyl group, and an organic acid anhydride; (b) adding to the solution a glycoside bearing an anomeric sulfoxide group; and (c) allowing a glycosylation reaction to proceed under conditions effective to produce the glycosidic linkage. In a preferred embodiment of the invention, a Lewis acid is present in the solution.